M-6328-C-T

Variant names:

• chrM-6328-C-T
• rs267606883
• unassigned_transcript_4799:c.425C>T

Variant summary

Our verdict is Uncertain significance. Variant got 3 ACMG points: 3P and 0B. PM2 PP5

In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Pathogenic (no stars).

• Frequency: Mitomap GenBank: Absent
• Consequence: COX1 missense
• Scores: Apogee2 Pathogenic 0.90
• Clinical Significance: Uncertain significance reviewed by expert panel P:1 U:1 EXIT-(Exercise-Intolerance)
• Conservation: PhyloP100: 7.55

Genes affected

COX1 (HGNC:7419): (mitochondrially encoded cytochrome c oxidase I) Contributes to cytochrome-c oxidase activity. Predicted to be involved in electron transport coupled proton transport and mitochondrial electron transport, cytochrome c to oxygen. Part of mitochondrial respiratory chain complex III and mitochondrial respiratory chain complex IV. [provided by Alliance of Genome Resources, Apr 2022]

ACMG classification

Verdict is Uncertain_significance. Variant got 3 ACMG points.

• PM2: No frequency data in Mitomap. Probably very rare.
• PP5: Variant M-6328-C-T is Pathogenic according to our data. Variant chrM-6328-C-T is described in ClinVar as [Pathogenic]. Clinvar id is 9671.Status of the report is no_assertion_criteria_provided, 0 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
COX1	unassigned_transcript_4799	c.425C>T	p.Ser142Phe	missense_variant	Exon 1 of 1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt

Frequencies

GnomAD4 exome Cov.: 0

We have no GnomAD4 genomes data on this position. Probably position not covered by the project.

Mitomap

EXIT-(Exercise-Intolerance)

ClinVar

Significance: Uncertain significance

Submissions summary: Pathogenic:1 Uncertain:1

Revision: reviewed by expert panel

Submissions by phenotype

Cytochrome c oxidase I deficiency Pathogenic:1

Mar 01, 2006

OMIM

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: literature only

- -

Mitochondrial disease Uncertain:1

Dec 21, 2023

ClinGen Mitochondrial Disease Nuclear and Mitochondrial Variant Curation Expert Panel, ClinGen

Significance: Uncertain significance

Review Status: reviewed by expert panel

Collection Method: curation

The m.6328C>T (p.S142F) variant in MT-CO1 has been reported in one individual to date with primary mitochondrial disease. This individual had a severe cardioencephalomyopathy resembling mitochondrial encephalomyopathy with lactic acidosis and stroke-like episodes (MELAS) and harbored the variant at >95% heteroplasmy in muscle (PMID: 16284789). P. denitrificans models support a deleterious functional impact of this variant (PS3_supporting; PMID: 16284789). The computational predictors APOGEE1 and APOGEE2 give a consensus rating of pathogenic and each had a raw score of 0.90 (Min=0, Max=1), which predict a damaging effect on gene function (PP3). This variant is absent in the GenBank dataset, Helix dataset, and gnomAD v3.1.2 (PM2_supporting). In summary, this variant meets criteria to be classified as uncertain significance for primary mitochondrial disease inherited in a mitochondrial manner. This classification was approved by the NICHD/NINDS U24 ClinGen Mitochondrial Disease Variant Curation Expert Panel on December 21, 2023. Mitochondrial DNA-specific ACMG/AMP criteria applied (PMID: 32906214): PS3_supporting, PM2_supporting, PP3. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
Apogee2	Pathogenic	0.90
Hmtvar	Pathogenic	0.86
AlphaMissense	Pathogenic	0.96
BayesDel_addAF	Uncertain	0.12	D
DEOGEN2	Benign	0.18	T
LIST_S2	Uncertain	0.92	D
MutationAssessor	Pathogenic	4.5	H
PROVEAN	Pathogenic	-4.7	D
Sift4G	Pathogenic	0.0	D
GERP RS		5.3
Varity_R		0.86

Splicing

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs267606883; hg19: chrM-6329;